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Volume 84 Issue 32 | pp. 21-27
Issue Date: August 7, 2006

Cover Stories

Battling Breast Cancer

By targeting multiple HER-family receptors, small-molecule drugs could fill the therapeutic gaps left by Herceptin
Department: Science & Technology

Most doctors aren't accustomed to being greeted like the Rolling Stones playing Madison Square Garden. But in spring 2005, at the annual meeting of the American Society of Clinical Oncologists (ASCO), the clinicians reporting results from a trial of Genentech's breast cancer drug Herceptin got a taste of the rock star treatment. A packed auditorium of oncologists broke out in applause upon hearing that adding the monoclonal antibody to a patient's chemotherapy regimen after surgery nearly halved the risk of the disease ever coming back. In a field of incremental progress−new cancer drugs often extend a patient's life by just months rather than years−the news was considered a major breakthrough.

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A Trojan Horse
GSK's Tykerb sneaks inside cancer cells before waging its attack on two HER receptors.
Credit: GlaxoSmithKline
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A Trojan Horse
GSK's Tykerb sneaks inside cancer cells before waging its attack on two HER receptors.
Credit: GlaxoSmithKline

Herceptin's success is based on its highly selective nature: The antibody binds to the HER2 receptor, a growth factor protein that is overexpressed in roughly 25% of breast cancer patients. First approved in the U.S. in 1998 to treat the most advanced cases of HER2-positive disease, the targeted therapy has proven over time to be a powerful weapon against even the earliest stage of that subset of breast cancer.

Yet even though many consider Herceptin to be a big leap in treating breast cancer in HER2-positive patients, there is still room for progress. "It's a hugely important drug, but there's a lot of opportunity to build on what was learned with Herceptin and to augment its activity," says Clifford A. Hudis, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center. "It's not like it's the last word; it's more like it's the first word."

Fast-forward to ASCO's 2006 meeting. There may not have been a standing ovation, but GlaxoSmithKline demonstrated that small-molecule cancer treatments such as its dual-kinase inhibitor Tykerb, also known as lapatinib, may give Herceptin a run for its money.

GSK unveiled data showing that Tykerb almost doubled the time it took for disease to progress in the sickest of patients with HER2-positive breast cancer: women for whom multiple therapies, including Herceptin, had failed. On the basis of those results, GSK expects to submit Tykerb for U.S. regulatory approval later this year, a move that could put the drug on the market in 2007.

The Tykerb results draw attention to a burgeoning class of small molecules that inhibit multiple receptors in the HER family, a tyrosine kinase signaling network that is implicated in certain types of breast cancer. The drugs bind to known targets, including the same HER2 receptor that Herceptin blocks, as well as to HER family members whose roles in the disease are still not completely understood.

Oncologists and pharmaceutical companies alike hope that, by widening the target range and offering a different mechanism of action, small molecules will fill the therapeutic gaps for patients with HER2-positive disease.

Companies developing multikinase inhibitors, including GSK, Wyeth, Array BioPharma, and Exelixis, see that therapeutic niche as a potentially lucrative market opportunity. Herceptin has enjoyed double-digit sales growth every year since its launch in 1998. Last year alone, Herceptin had a 58% spike in sales to $764 million after the release of the data for early-stage breast cancer. And because the small molecules target multiple receptors, that market opportunity could extend beyond the HER2-positive subset to other kinds of breast cancer, as well as other tumor types, such as lung cancer.

HUDIS
Credit: Memorial Sloan-Kettering Cancer Center
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HUDIS
Credit: Memorial Sloan-Kettering Cancer Center

Hudis points out that, even though Herceptin hugely lowers the risk of breast cancer returning in HER2-positive patients, there is still the matter of the other half of the time when the disease comes back. And most patients, over time, develop a resistance to the antibody. "The truth is that, in the metastatic setting, even though Herceptin works, it almost always stops working," he notes. Moreover, Herceptin cannot cure cancer that has demonstrably spread to other parts of the body.

This is where small-molecule drugs come in. Whereas Herceptin is highly specific to the HER2 receptor, scientists now understand that the HER2 story is not just about the receptor protein. Each signal is sent through a series of intermediate steps, "and each one of those steps represents multiple opportunities to intervene," Hudis explains.

Multikinase inhibitors in development for breast cancer try to disrupt as many points in the cell-signaling pathway as possible by blocking two or more of the four members of the HER family. In the case of GSK's Tykerb, both HER2 and HER1 are taken out.

There was a time when the idea of developing a drug that could hit multiple kinase receptors at once was dismissed as too risky. The belief was that a drug with such "broad selectivity" would be too toxic. However, evidence is emerging that not only can the body tolerate a multipronged attack, but that the strategy more appropriately addresses the complex way cells talk to one another.

Cancer cells need to communicate to grow. The "phone lines" are turned on when the four HER receptors dimerize, either with the same type of receptor (HER2-HER2) or with another member of the family (HER2-HER1 or HER2-HER4, for example). It is widely believed that Herceptin can turn off only homodimers; at the same time, evidence is growing that the heterodimers are also linked to HER2-positive breast cancer. Multikinase inhibitors can turn off both homodimers and heterodimers.

"A decade or more ago, when Herceptin was developed, most scientists believed that HER2-HER2 binding drove HER2-positive breast cancer," says Jeffrey Bloss, group medical director for biooncology at Genentech. "With time, we have begun to question whether other HER-family receptors play any role in the disease."

Julie R. Gralow, associate professor of medical oncology at the University of Washington and Fred Hutchinson Cancer Research Center, in Seattle, recommends caution: "We really need to test the full efficacy and toxicity to see if blocking more of the HER family is a benefit. In theory it should be, but what plays out in the lab isn't always what happens in patients."

In addition to targeting more points along the disease pathway, multikinase inhibitors also have distinct mechanistic advantages over biologics. For example, they act in a sense like a Trojan horse, says Steven Stein, director of clinical development at GSK's Oncology Medicine Development Centre. They wait to be allowed inside the cell before staging their attack on disease-signaling pathways. Monoclonal antibodies, in contrast, are too bulky and conspicuous to get inside the cell, which means Herceptin must wage its offensive externally.

The catch with Herceptin's strategy is that cancer is itself stealthy and can eventually figure out how to undermine the drug by slicing off the external part of the receptor. Having eliminated a place for the antibody to bind, cancer cells can again proliferate. "In that scenario, Tykerb will have a potential advantage, because an antibody can't work against a cleaved receptor," Stein says.

Another advantage may benefit the approximately 30% of patients with HER2-positive breast cancer who do not succumb to breast cancer itself but rather to the disease spreading to the brain.

GRALOW
Credit: ASCO
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GRALOW
Credit: ASCO

Early data also suggest that small molecules can cross the blood-brain barrier, a feat monoclonal antibodies are too cumbersome to achieve. "There is pretty good evidence that big molecules don't cross the blood-brain barrier," and therefore the brain becomes a sanctuary for cancer cells, Hudis says. According to Gralow, Herceptin can have an impact on metastatic disease in the brain only when it is so advanced, the cancer so big and bulky, that it disrupts the blood-brain barrier and allows the antibody through.

Small molecules, on the other hand, may be able to prevent that advanced disease from ever happening. "When you're talking about microscopic disease, these small-molecule drugs can potentially delay or totally eliminate tumor growth," Gralow notes.

GSK released preliminary Phase II data at ASCO suggesting that Tykerb can get past that blood-brain blockade, though more studies need to be completed before researchers can understand whether the drug's mobility has a real impact on the spread of disease.

Developers of small-molecule multikinase inhibitors also say their products can provide substantial quality-of-life benefits over biologics. For example, small molecules offer the opportunity for patients to take a pill at home, whereas biologics must be administered intravenously in a hospital. This benefit is enormous, because HER inhibitors keep cancer from growing rather than kill it outright, and some patients will be on these drugs indefinitely to keep their disease in check.

"We have patients who stay on Herceptin for five or 10 years in the metastatic setting," Gralow says. The Genentech drug is approved for weekly intravenous injection. Although it appears possible to get the same benefit from dosing once every three weeks, even that regimen can be inconvenient in the long term, she adds.

With a sound argument for the potential benefit of multikinase inhibitors to patients with HER2-positive breast cancer, it is not surprising that a number of companies have jumped on the drug development bandwagon.

The complexity of the HER family signaling network has led to a spectrum of approaches to inhibiting tyrosine kinase receptors. Each is based on the same principle: blocking all avenues of cancer growth. An antibody can interrupt just one pathway, but cancer is evasive and will try to find a side road. GSK's Tykerb leaves cancer with fewer options by hitting two of the four HER receptors. Other small molecules in development are setting up even more roadblocks.

Wyeth is hoping to leave cancer with nowhere to turn. The company's multikinase inhibitor HKI-272 hits what it believes to be the active members of the HER family: HER1, HER2, and HER4.

"The distinguishing point between HKI-272 and the other kinase inhibitors is that our compound is an irreversible binding inhibitor," says Sridhar K. Rabindran, associate director of oncology and discovery at Wyeth. HKI-272 forms a covalent bond with a critical cysteine residue, permanently inactivating the enzyme so it cannot be recognized by the cell, Rabindran explains.

That irreversible binding mechanism has already proven important in lung cancer, the other indication for which HKI-272 is being studied. Lung cancer patients tend to develop a resistance to AstraZeneca's Iressa and Genentech's Tarceva, both small molecules that inhibit the HER1 pathway, one target of HKI-272.

The Wyeth drug appears to work against the cells carrying that resistance-conferring mutation, Rabindran says, making it a good therapeutic option for patients whose disease has progressed despite those therapies. But it remains to be seen whether the binding mechanism will give HKI-272 a leg up over other breast cancer treatments.

As with Tykerb, studies of HKI-272 to date have been conducted with HER2-positive patients who have been previously treated with Herceptin. Early-phase trials have been promising. Of 23 evaluable patients in a Phase I trial to treat breast cancer, seven had confirmed partial responses, "a high rate when you consider all of these patients had multiple prior rounds of therapy, including Herceptin," Rabindran notes.

On the basis of those results, Wyeth launched Phase II trials of HKI-272 to treat metastatic breast cancer in December. The firm has yet to determine a timeline for their completion and the subsequent initiation of Phase III studies.

While Wyeth is aiming to shut down the entire HER pathway with its compound, South San Francisco-based Exelixis is trying to place roadblocks along two different tyrosine kinase signaling pathways. The biotech company has a potential breast cancer drug in development that attacks two members of the HER2 pathway, as well as the vascular endothelial growth factor, or VEGF, receptor. In essence, XL647 combines the activities of Herceptin, Iressa, and Genentech's VEGF-inhibiting antibody Avastin into one orally active small molecule.

Exelexis obtained encouraging results in Phase I trials to treat solid tumors, and it now expects to initiate a Phase II trial of XL647 to treat breast cancer later this year. Similar to Herceptin, XL647 is likely to prove effective in the HER2-positive population. In addition, the company believes that by also targeting a receptor related to blood vessel growth, the drug could find utility in the larger breast cancer population.

"Part of the logic of a compound like XL647 that has activity against both the HER2 axis and the VEGF axis is that you're liable to see broader activity against tumor types that may be driven to a minor extent by HER2 but have some stronger vascular component," says Michael Morrissey, executive vice president of discovery at Exelixis.

If Exelixis' approach turns out to work better than the dual-kinase inhibition offered by Tykerb, GSK is not going to lose. XL647 is part of a broad collaboration between Exelixis and GSK under which Exelixis develops certain small-molecule therapeutics through Phase II, and GSK has the option to cherry-pick drugs for licensing.

Meanwhile, Boulder, Colo.-based Array BioPharma is hoping to improve on GSK's success. The company's most advanced drug, ARRY-334543, is a dual-kinase inhibitor designed around the structure of Tykerb.

"We liked the idea of hitting the entire HER family, so we looked at the lapatinib compound and asked, 'How do we create a best-in-class HER2 inhibitor?' " explains Kevin Koch, president and chief scientific officer of Array.

Their reasoning was that lapatinib, though potent in a cellular assay, has "significant liabilities," Koch says. The GSK compound is fairly insoluble, which means that administering the highest tolerated dose is a challenge. "They are dosing upward of 1.6 g of the molecule in patients," he says, noting the data show that the drug is not well-absorbed and is short-lived in plasma. Array is convinced that its molecule addresses those challenges while also offering stronger binding affinity than lapatinib.

Though ARRY-334543 is designed around lapatinib, Array is advancing the drug first in lung cancer and other tumors for which it is less likely to compete with GSK's drug. The company's scientific panel is meeting this summer to determine "the competitive positioning" of the molecule, which could eventually include breast cancer, Koch says.

Despite their built-in advantages over biologics, multikinase inhibitors in development are not going to knock antibodies out of the market. "It is a huge and long journey to say lapatinib is an oral Herceptin," says William M. Burns, chief executive officer of Roche's pharmaceutical business. Roche has a majority stake in Genentech and markets Herceptin outside the U.S.

Although Tykerb and other multikinase inhibitors are now being tested in patients with advanced stages of breast cancer, it can take years before a new drug can be proven effective against early stages of the disease. Roche began studying the adjuvant, or after-surgery, use of Herceptin in 1990, and it took eight years to collect enough data to demonstrate its efficacy against a placebo, Burns says. To date, the monoclonal antibody has been tested in more than 13,000 patients.

In addition, the bar is already set fairly high. To get into the market, new drugs will have to show that they work as well as, if not better than, Herceptin, which is already a very effective drug.

Burns also suggests that patients in the Tykerb study may have been experiencing a residual benefit from treatment with Herceptin, since they were dosed with the small molecule after stopping treatment on the biologic.

Furthermore, Genentech is developing an antibody, pertuzumab, that addresses some of the same limitations of Herceptin that the small molecules are addressing. Like Herceptin, pertuzumab locks into the HER2 receptor from outside the cell, but pertuzumab sits in the "arm," the site where HER2 can bind with other HER molecules, Genentech's Bloss explains. This inhibits heterodimers from forming and could enable the drug to be used in combination with Herceptin to disrupt the same range of signaling pathways that the small molecules affect.

Competing companies may make it seem that the breast cancer arena is shaping up to be a battle between David and Goliath, but most oncologists see the small-molecule drugs working in conjunction with Herceptin, and possibly pertuzumab, to get the best results for the patient. One way the drugs could work is in sequence, thereby keeping an option open for patients who develop resistance to one type of treatment.

Another strategy might be to use the drugs in combination to get at HER2 from both outside and inside the cell. "It might be that synergy is the best way to shut down everything," the University of Washington's Gralow reasons.

In fact, GSK has published preclinical data suggesting that using Tykerb and Herceptin together can have a synergistic effect. "Lapatinib is a different molecule entirely," Stein notes, so there might be times when it is best used in combination with the biologic, and other scenarios where sequential use is more appropriate. "All of those strategies have strong biology to back them up, and they all will be tested," he adds.

The data that will be used in GSK's New Drug Application to the Food & Drug Administration are based on giving Tykerb as a monotherapy to patients who have seen their disease progress after being treated with Herceptin. The company is now conducting a Phase III trial to see if there is a benefit to using Tykerb in combination with Herceptin.

Commercially, multikinase inhibitors have one distinct advantage over Herceptin. By targeting multiple pathways, they all show potential to treat a range of tumor types, particularly lung cancer. Some people also hope that these drugs will show activity in breast cancer patients who aren't HER-2 positive.

"By no means are we limiting our development program to only HER2-positive patients," GSK's Stein says. Though the most advanced trials for Tykerb are focused on HER2-positive patients, Stein says there is evidence that the drug could find use in the wider population of breast cancer patients. "Although the response rate was higher in the HER2-positive population, there were responders in the HER2-negative population as well," he notes.

To date, drugs that inhibit only HER1, such as Iressa and Tarceva, have not been shown to be active against breast cancer. The inactivity leads oncologists to believe the HER1 pathway does not play a major role in the disease, Gralow says.

Yet evidence is emerging that the HER1 pathway is critical in a few smaller HER2-negative groups of breast cancer patients. Multikinase inhibitors show promise in patients with inflammatory breast cancer, and some data indicate that pankinase inhibitors may be effective in treating a rare and aggressive subtype of breast cancer known as "triple negative," because patients are estrogen-receptor-, progesterone-receptor-, and HER2-negative. In these patients, the cancer cells tend to overexpress HER1, a pathway knocked out by the drugs from GSK, Wyeth, Exelixis, and Array.

GSK is interested in studying Tykerb in that subpopulation, but the company also acknowledges that a lot of firms are also eyeing the role of HER1 in triple-negative breast cancer. Already-approved drugs such as Iressa, Tarceva, and ImClone's Erbitux could be used to target the disease.

In the end, having a variety of small-molecule drugs targeting different receptors is "really exciting−a huge advance," Gralow says. With the range of treatment options opening up, Gralow believes that in just a few years, breast cancer will be treated in different, much more specific ways. "We'll be using less chemotherapy and getting less toxicity," she says.

 
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